Current Topics in Medicinal Chemistry - Volume 9, Issue 11, 2009

It is a pleasure to recognize the present milestone of 10 years of continuous publication for this journal, Current Topics in Medicinal Chemistry (CTMC). CTMC has grown beyond expectations and is now among the top five in the field of medicinal chemistry in terms of Impact Factor. CTMC was originally conceived as a secondary review journal in which top areas of research in the fields of medicinal chemistry and allied disciplines could be covered thematically, much in the same way as a symposium at a scientific meeting is organized. CTMC has an electronic version as do almost all journals, but has resisted the temptation to eliminate print copies - a subscriber can still page through his or her personal copy and browse as they wish. This 10th-year celebration issue contains six manuscripts. The first five were selected because the authors had authored articles in CTMC which were among the elite group of being in the top cited manuscripts for CTMC during the past 10 years. They have rewritten the original topics providing updates and new perspectives. The first by Gary Caldwell and colleagues describes the important topic of the use of Absorption, Distribution, Metabolism and Excretion (ADME) testing in drug discovery to improve the overall odds of success. The second manuscript by Karl Drlica et al. entails a particular structural class important in anti-infective research, the quinolones. The third by Christina Gianoulakis describes the endogenous opioids and their relevance in states of addiction. The fourth article by Yves Pommier describes a particular class of agents for the treatment of AIDS, the HIV-1 integrase inhibitors. The fifth manuscript by Gary Schieven reviews p38 kinase as a therapeutic target in inflammation. Finally, Bruce Maryanoff describes the discovery of topiramate, a multi-billion dollar drug he personally invented. Dr. Maryanoff is now retiring after a distinguished career with Johnson & Johnson. Credit must go to the many CTMC Guest Editors during the past 10 years who have provided rigor and expertise to each issue. On a personal level, I thank Dr. Matthew Honan of Bentham Science Publishers for the opportunity to be involved with CTMC, and to Ms. Ambreen Wasim of the Bentham editorial office for her many efforts from the beginning. Thanks to Dr. Honan and Bentham for sponsoring a CTMC annual dinner in each of the past nine years at the fall meeting of the American Chemical Society. These have been enjoyable and memorable events, starting first at the top of the Hancock Tower in Chicago and most recently held at a great restaurant in Washington, DC. There is no greater time than the present to be a scientist, given the research tools we have to work with and the towering efforts of others upon which we build. Medicinal Chemistry is a wonderful discipline because it interfaces with other activities including pharmacology, intellectual property, process chemistry, preclinical and clinical development, and many others.

Integrating physicochemical, drug metabolism, pharmacokinetics, ADME, and toxicity assays into drug discovery in order to reduce the attrition rates in clinical development is reviewed. The review is organized around three main decision points used in discovery including hit generation, lead optimization and final candidate selection stages. The preclinical strategies used at each decision point are discussed from a drug discovery perspective. Typically, preclinical data produced at these stages use lower throughput assays, smaller amounts of compounds and operate within a timeframe that is consistent with the iterative cycle of most drug discovery research projects. Understanding the false positive rates of these drug discovery preclinical assays is a must in reducing attrition rates in development.

The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallography shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concentrations are above the MIC and below the MPC, as observed with static agar plate assays, dynamic in vitro systems, and experimental infection of rabbits. The gap between MIC and MPC can be narrowed by compound design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported.

There is significant experimental evidence implicating the endogenous opioid system (opioid peptides and opioid receptors) with the processes of reward and reinforcement. Indeed, many behaviors associated with reward and reinforcement, for example feeding behavior, are controlled by distinct components of the endogenous opioid system located in relevant brain regions. It has also been shown that regardless of their initial site of action many drugs of abuse, such as morphine, nicotine, cocaine, alcohol and amphetamines, induce an increase in the extracellular concentration of dopamine in the nucleus accumbens. This, increased secretion of dopamine in the nucleus accumbens seems to be a common effect of many drugs of abuse, and it was proposed that may mediate their rewarding and reinforcing properties. Furthermore, activation of μ opioid receptors in the ventral tegmental area, or of μ and δ opioid receptors in the nucleus accumbens enhances the extracellular concentration of dopamine in the nucleus accumbens. Thus, stimulation of the activity of distinct components of the endogenous opioid system either by opioid or by other drugs of abuse, may mediate some of their reinforcing effects. In this review article, a brief description of the endogenous opioid system and its implication in the processes of reward and reinforcement of opioid and other drugs of abuse will be presented. Furthermore, the use of opioid antagonists in the treatment of drug addiction will be discussed. Special emphasis will be given to ethanol addiction, the drug mainly studied in my laboratory.

Integrase (IN) is the newest validated target against AIDS and retroviral infections. The remarkable activity of raltegravir (Isentress®) led to its rapid approval by the FDA in 2007 as the first IN inhibitor. Several other IN strand transfer inhibitors (STIs) are in development with the primary goal to overcome resistance due to the rapid occurrence of IN mutations in raltegravir-treated patients. Thus, many scientists and drug companies are actively pursuing clinically useful IN inhibitors. The objective of this review is to provide an update on the IN inhibitors reported in the last two years, including second generation STI, recently developed hydroxylated aromatics, natural products, peptide, antibody and oligonucleotide inhibitors. Additionally, the targeting of IN cofactors such as LEDGF and Vpr will be discussed as novel strategies for the treatment of AIDS.

The p38 kinase plays a central role in inflammation, and it has been the subject of extensive efforts in both basic research and drug discovery. This review summarizes the biology of the p38 kinase with a focus on its role in inflammation. The p38 kinase regulates the production of key inflammatory mediators by cells of the innate immune system, including TNFα, IL-1β, and COX-2. In addition, p38 also acts downstream of cytokines such as TNFα, mediating some of their effects. Recently p38 has also been found to play a role in responses of T cells, including Th17 and regulatory T cells. Consistent with its important role in inflammation, recent evidence suggests cells may utilize a variety of feedback mechanisms to regulate and maintain p38 signal transduction. The biological processes regulated by p38 kinase suggest both a wide variety of potential indications for inhibitors and a level of complexity that has proven challenging to drug discovery efforts around this target.

TOPAMAX® (topiramate) 1, is a broad-spectrum anticonvulsant that has been marketed worldwide for the treatment of epilepsy and migraine. We discovered this blockbuster drug serendipitously in a project that originally sought a new antidiabetic agent. Topiramate has useful neurological effects that derive from multiple CNS mechanisms of action, but it is basically a “neurostabilizer” by virtue of attenuating the excitability of brain neuronal pathways. During its extensive clinical use, topiramate was also found to possess antimetabolic dysfunction activity, which could be applicable in the treatment of diabetes and obesity. This article discusses research results and events surrounding the discovery and development of topiramate.